6. Project Summary/Abstract This proposal addresses the research objectives identified in PA-07-282 (Mechanisms, Models, Measurement, and Management in Pain Research) and specifically targets the topics of Biobehavioral Pain, Pain Management, and Translational Pain Research. We propose a series of studies in the laboratory pain setting (thermal and/or electrical pain in healthy volunteers) designed to test three specific and related hypotheses exploring the neurophysiologic mechanisms that underlie immersive Virtual Reality (VR) as a non- pharmacologic pain management technique. The concurrent pharmacologic manipulation of VR analgesia in these studies will likely yield mechanistic insights that will improve future clinical application of VR exposure, and make immersive VR a more effective analgesic tool for more patients. The ideal clinical use of VR will likely be as one component of a multimodal analgesia regimen, administered in combination with pharmacologic analgesics. However, the additive and potential synergistic analgesic effects of these techniques have yet to be examined. This proposal focuses on the concomitant use of VR exposure and systemic analgesic agonists or antagonists known to affect pain perception, and builds on previous work by our group that has compared concurrent subjective and neuroimaging evidence of analgesia with immersive VR and systemic opioid therapy. This proposal has two broad goals: (1) to test specific hypotheses concerning the neurophysiologic mechanisms of VR analgesia, using concomitant subjective and functional brain imaging (fMRI) assessments of the pain experience, and (2) to determine the potential additive and/or synergistic analgesic effects of combined immersive VR and pharmacologic analgesic administration. These goals will be met through three Specific Aims: (1) To determine the extent to which subjective analgesic effects of VR analgesia are inhibited (or not) by opioid receptor antagonism with naloxone; (2) To determine the comparative and additive effects of immersive VR and N-methyl-D-aspartate (NMDA) antagonism with low- dose ketamine (at a sub-anesthetic dose devoid of hallucinatory effects, but associated with analgesia, expansive mood, and heightened perception); (3) To determine the comparative effects of immersive VR and NMDA antagonism with low-dose ketamine on pain-related brain activity in standard brain regions of the pain matrix, as well as in brain structures associated with modulation of the pain experience, and to correlate observed brain activity with subjective reports of the pain experience. Information gained from the proposed studies will guide (1) future investigations that define specific analgesic mechanisms of immersive VR, (2) the thoughtful clinical combination of VR exposure and pharmacologic analgesics in a multimodal analgesia approach to reducing procedural pain, and (3) future assessments of the cost-effective application of VR systems designed to maximize the analgesic effect of immersive VR in various clinical pain settings.